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F W Chen

Publications and source records attributed to F W Chen.

At least 19 recordsLinked to original sources
PubMed2000

Transmembrane molecular pump activity of Niemann-Pick C1 protein.

Niemann-Pick C1 (NPC1) disease is characterized by cholesterol accumulation in lysosomes and aberrant feedback regulation of cellular cholesterol homeostasis. We provide evidence that the NPC1 protein has homology with the resistance-nodulation-division (RND) family of prokaryotic permeases and may normally function as a transmembrane efflux pump. Studies of acriflavine loading in normal and NPC1 fibroblasts indicated that NPC1 uses a proton motive force to remove accumulated acriflavine from the endosomal/lysosomal system. Expression of NPC1 in Escherichia coli (i) facilitated the transport of acriflavine across the plasma membrane, causing cytosolic accumulation, and (ii) resulted in transport of oleic acid but not cholesterol or cholesterol-oleate across the plasma membrane. These studies establish NPC1 as a eukaryotic member of the RND permease family.

Acriflavine↗
PubMed1999

Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network.

Niemann-Pick type C (NPC) disease is a severe cell lipidosis characterized by the accumulation of unesterified cholesterol in the endosomal/lysosomal system. Recently the primary disease-causing gene, NPC1, was identified, but few clues regarding its potential function(s) could be derived from its predicted amino acid sequence. Therefore, efforts were directed at characterizing the subcellular location of the NPC1 protein. Initial studies with a FLAG-tagged NPC1 cDNA demonstrated that NPC1 is a glycoprotein that associates with the membranes of a population of cytoplasmic vesicles. Immunofluorescence microscopy using anti-NPC1 polyclonal antibodies confirmed this analysis. Double-label immunofluorescence microscopy and subcellular fractionation studies indicated that NPC1 associates predominantly with late endosomes (Rab9 GTPase-positive vesicles) and, to a lesser extent, with lysosomes and the trans-Golgi network. When cholesterol egress from lysosomes was blocked by treatment of cells with U18666A, the NPC1 location shifted from late endosomes to the trans-Golgi network and lysosomes. Subcellular fractionation of liver homogenates from U18666A-treated mice confirmed these observations. These data suggest that U18666A may inhibit the retrograde transport of NPC1 from lysosomes to late endosomes for subsequent transfer to the trans-Golgi network.

Androstenes↗
PubMed1999

Ribosomal proteins in cell proliferation and apoptosis.

Ribosomal proteins have the complex task of coordinating protein biosynthesis to maintain cell homeostasis and survival. Recent evidence suggests that a number of ribosomal proteins have secondary functions independent of their involvement in protein biosynthesis. A number of these proteins function as cell proliferation regulators and in some instances as inducers of cell death. Specifically, expression of human ribosomal protein L13a has been shown to induce apoptosis, presumably by arresting cell growth in the G2/M phase of the cell cycle. In addition, inhibition of expression of L13a induces apoptosis in target cells, suggesting that this protein is necessary for cell survival. Similar results have been obtained in the yeast Saccharomyces cerevisiae, where inactivation of the yeast homologues of L13a, rp22 and rp23, by homologous recombination results in severe growth retardation and death. In addition, a closely related ribosomal protein, L7, arrests cells in G1 and also induces apoptosis. Thus, it appears that a group of ribosomal proteins may function as cell cycle checkpoints and compose a new family of cell proliferation regulators.

Animals↗
PubMed1998

Differential gene expression in apoptosis: identification of ribosomal protein 23K, a cell proliferation inhibitor.

Gene expression during the camptothecin-induced apoptotic death of human leukemic U937 cells and mouse T-cell hybridoma QW4.1 cells was studied by the mRNA differential display technique. Ten clones were confirmed to be differentially expressed, nine of which encoded novel sequences. One clone, U3.2, was induced approximately 10-fold in camptothecin-treated cells and was found to be identical to a highly basic 23-kDa human protein which contains basic leucine zipper-like motifs and has recently been identified as the human homologue of the rat ribosomal protein L13a. Northern blot analysis revealed a major mRNA of approximately 0.9 kb and a minor mRNA of approximately 1.3 kb. Overexpression of a full-length 23K cDNA, tagged with a FLAG sequence, in COS-7 cells revealed a predominantly nucleolar localization and the absence of any 23K protein from the cytoplasm. Subsequent transfection studies, using antisense phosphorothioate-modified oligonucleotides, revealed that inhibition of 23K expression results in an increased cell proliferation and greater sensitivity of U937 cells to the effects of camptothecin-induced cell death. Upregulation of 23K expression using a cDNA construct resulted in a decrease in cell proliferation and growth arrest, suggesting a role for 23K protein as a proliferation checkpoint following a cellular insult.

Animals↗
PubMed1995

Noninvasive localization of experimental atherosclerotic lesions with mouse/human chimeric Z2D3 F(ab')2 specific for the proliferating smooth muscle cells of human atheroma. Imaging with conventional and negative charge-modified antibody fragments.

BACKGROUND: A murine monoclonal antibody designated Z2D3 (IgM) generated against homogenized human atherosclerotic plaques was demonstrated to be highly specific for proliferating smooth muscle cells. The primary clone subsequently was genetically engineered to provide a mouse/human chimeric antibody with human IgG1 constant region expressed in a rat myeloma cell line. The resulting Z2D3-73.30 chimeric retained the immunoreactivity relative to the parent Z2D3-IgM and was pepsin-digested to yield F(ab')2. 111In-labeled chimeric Z2D3 F(ab')2 was then used for noninvasive imaging of experimental atherosclerotic lesions. To improve the imaging characteristics, we modified chimeric Z2D3 F(ab')2 fragments to carry a high negative charge. Improved visualization of targets with 111In-labeled, negatively charged, polymer-modified antibodies most probably is the result of faster blood clearance and a decrease in nontarget background activity. METHODS AND RESULTS: Experimental atherosclerotic lesions were induced in rabbits by deendothelialization of the infradiaphragmatic aorta followed by a 6% peanut oil-2% cholesterol diet. After 12 weeks, localization of the conventionally labeled 111In-Z2D3 F(ab')2 (24 Mbq [650 microCi]/500 to 750 micrograms) (n = 4) was compared with 111In-labeled, negatively charged, polymer-modified Z2D3 F(ab')2 (24 Mbq [650 microCi]/25 to 50 micrograms) in eight atherosclerotic rabbits. Three control rabbits also received radiolabeled polymer-modified Z2D3. Ten rabbits with atherosclerotic lesions received 111In-labeled nonspecific human IgG1 F(ab')2 with (n = 6) or without (n = 4) negative charge modification. Atherosclerotic lesions were visualized in all rabbits with the conventional Z2D3 F(ab')2 at 48 hours. However, unequivocal lesion visualization was possible at 24 hours only with negatively charged, polymer-modified Z2D3 F(ab')2. Quantitative uptake of F(ab')2 fragments was essentially determined by the presence of atherosclerotic lesions (F1.37 = 69.8; P < .0001) and the specificity of the antibody (F1.37 = 36.6; P < .0001). Uptake of the conventional Z2D3 in atherosclerotic lesions (mean +/- SEM percent injected dose per gram, 0.112 +/- 0.024%) was six times higher than background activity in the normal aortic segments (nondenuded thoracic aorta; mean percent injected dose per gram, 0.019 +/- 0.003%). Uptake of the conventional Z2D3 was also significantly higher than that of nonspecific human IgG1 F(ab')2 (0.027 +/- 0.004%). Specific uptake of the conventional Z2D3 in the lesions was comparable to the charge-modified Z2D3 uptake (0.084 +/- 0.017; P = .20). Uptake of negative charge-modified Z2D3 in the lesions was significantly higher than in the corresponding background activity in normal thoracic aorta (0.021 +/- 0.002). Uptake of negative charge-modified Z2D3 F(ab')2 in the lesions was higher than the uptake of negative charge-modified nonspecific IgG1 F(ab')2 (0.020 +/- 0.002) in the lesions. Uptake of charge-modified Z2D3 in the atherosclerotic lesions was also significantly higher than the corresponding regions of the aorta of the control rabbits (0.017 +/- 0.002; F1.18 = 27.9; P = .0001). There was, however, no difference in the specific lesion uptake of negative charge-modified Z2D3 at 24 hours (0.079 +/- 0.014) and 48 hours (0.084 +/- 0.0017; P = .99) after intravenous administration. Nontarget organ activities were lower with negative charge-modified 111In-labeled Z2D3 F(ab')2 than with the conventional Z2D3 F(ab')2. Mean kidney activity was fourfold less with the modified (0.45 +/- 0.06) than with the conventionally radiolabeled (1.67 +/- 0.264; P = .001) Z2D3 F(ab')2.

Animals↗
PubMed1992

Clinical experience of octreotide in the treatment of acromegaly.

To evaluate the efficacy and safety of octreotide (a somatostatin analogue) in the treatment of acromegaly, 10 patients were injected subcutaneously with octreotide, 50 micrograms, thrice daily before each meal for two days, followed by 100 micrograms thrice daily for six months. One case dropped out at the initial stage because of diarrhea, and another quit due to a lack of improvement in headaches after treatment for three months. Eight patients completed the study. The results showed that the circumference of the fourth finger and hand volume significantly decreased after treatment. Laboratory data demonstrated that serum growth hormone (GH) and somatomedin-C levels also decreased significantly. However, in six patients without a history of trans-sphenoidal adenomectomy, the serum GH and somatomedin-C levels returned to normal in only one case who had a serum GH level < 20 mU/L before treatment. In the oral glucose tolerance test, paradoxic elevation of GH subsided after treatment. In the TRH test, paradoxic elevation of GH improved after treatment. In the bromocriptine test, octreotide had a synergistic effect on the suppression of GH. All cases had the side effect of injection pain, especially at the initial stage. An increase in intestinal peristalsis and bowel movement occurred in the first week, but symptoms later subsided. Two out of these eight patients had gallbladder sludge after six months of treatment. In conclusion, octreotide is effective in the treatment of acromegaly; however, it is better used in patients who have serum GH levels < 20 mU/L, or after a trans-sphenoidal adenomectomy, and may be combined with bromocriptine to treat the patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1992

Plaque-associated immune reactivity as a tool for the diagnosis and treatment of atherosclerosis.

In summary, we have confirmed that a specific humoral immune reactivity involves human atherosclerotic plaque. By isolating some of the autoantigens and employing them in prototype immunoassays, we have been able to measure for the presence of plaque-specific antibodies. Extracted plaque antigens have also served as immunogens in monoclonal antibody generation. These have shown early promise as plaque-directed in vivo targeting agents. Further scientific evaluation and reagent development remains before the practical utility of employing such reagents or methods in the care of patients with atherosclerosis-related diseases can be ascertained.

Animals↗
PubMed1991

Decreased bone mineral density in patients with prolonged thyrotoxicosis before and after treatment.

To investigate the effects of prolonged thyrotoxicosis, we measured the bone mineral densities (BMD) of 24 untreated patients who had suffered from symptoms of thyrotoxicosis for at least 1 year. We also recruited 116 healthy Chinese women residing in the Taipei area as normal controls. The BMDs of these 24 patients for the whole body skeleton, lumbar spine, femoral neck, greater trochanter and Ward's triangle were all significantly lower than those of normal controls (one sample t-test, two-tailed alternative). Older patients had lower absolute values and a trend towards more severe bone loss, which was most significant at the femoral trochanter and Ward's triangle (p less than or equal to 0.05). The decrease in BMD was more pronounced in the vertebral bodies than in the proximal femur for all patients, implying predominantly trabecular bone loss in this disease. The BMDs of 10 patients were reevaluated 1 year after successful medical treatment. These 10 patients had remained euthyroid for 1 year with antithyroid drugs and showed a small, but significant, improvement in their BMDs at the lumbar spine and the proximal femur on reevaluation. However, the recovery was far from complete. Our findings suggest that thyrotoxicosis causes a remarkable loss of bone mineral, which cannot be compensated for after 1 year of successful treatment. Thus, early diagnosis and therapeutic intervention are important for preventing osteoporotic fractures, especially in elderly patients.

Adult↗
PubMed1991

Effect of cranial irradiation on hypothalamus-pituitary function: follow-up study one year after radiotherapy.

Hypothalamic pituitary functions were studied in 24 patients before, 6 months after and 1 year after cranial irradiation with or without radiosensitizing chemotherapy for nasopharyngeal carcinoma (NPC). The estimated average total dose was 5,000 cGy to the hypothalamus and pituitary gland. The radiosensitizing chemotherapy used was endoxan, 4,900 +/- 873 mg (mean +/- SD) and/or methotrexate, 113 +/- 30 mg. All patients had normal pituitary function before radiotherapy. There was a progressive increase in baseline serum thyrotropin (TSH) after radiotherapy. The basal serum follicle stimulating hormone (FSH) was significantly increased 6 months after radiotherapy and remained so at 1 year after radiotherapy. The TSH response to thyrotropin-releasing hormone (TRH) also progressively increased after radiotherapy, suggesting primary hypothyroidism due to neck irradiation. The peak serum TSH response to TRH became delayed after radiotherapy, suggesting a defect in TRH release. In male patients who did not receive chemotherapy, the LH response to luteinizing hormone-releasing hormone (LHRH) decreased after radiotherapy. After an initial rise in the FSH response to LHRH 6 months after radiotherapy, there was a reduction in the FSH response at 1 year. This suggests a defect in LHRH pulsatile release. However, in male patients who received radiosensitizing chemotherapy, both the FSH and LH responses to LHRH had declined at 1 year after radiotherapy, as compared with their responses at 6 months. However, these were still higher than those obtained before radiotherapy. This suggests further GnRH neuron damage, which was previously masked by chemotherapy-induced primary hypogonadism. The adrenocorticotropic hormone (ACTH) response to ovine corticotropin-releasing hormone (CRH) had not changed further at 1 year after radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Idiopathic hypothalamic hypogonadism with polyostotic fibrous dysplasia: report of a case.

A 48-year-old man with Albright's syndrome and hypogonadism is presented. Eunuchoid status, hypogenitalia and hypogonadotropinemia were associated with pathological fracture and deformity of bones. GnRH test revealed minimal LH response and delayed FSH peak. After pulsatile GnRH priming, the LH response to GnRH increased. Results of other provocative hypothalamic-pituitary tests were consistent with hypothalamic lesions. To the best of our knowledge, this is the first report of a male patient with Albright's syndrome and idiopathic hypothalamic hypogonadism. The hypothesis of endocrinopathy and its relation to other components of this syndrome were reviewed.

Fibrous Dysplasia, Polyostotic↗
PubMed1990

Albright's syndrome with acromegaly and Hashimoto's thyroiditis: report of a case.

The case of a 35-year-old woman with Albright's syndrome, acromegaly and Hashimoto's thyroiditis is presented. She had noted deformity of the left mandible and chest from childhood. She developed persistent galactorrhea and amenorrhea after the delivery of her second child. X ray of the skull, and a head CT, revealed a pituitary tumor and fibrous dysplasia of the left mandible, sphenoid, zygomatic bone and pteryoid plate. Serum GH and PRL levels were markedly elevated. She received recontouring surgery of the left mandible, and a pathological examination confirmed the diagnosis of fibrous dysplasia. Chest X ray also showed fibrous dysplastic change of the left 4th, 5th, 6th and 7th ribs and left clavicle. Because of poor response to bromocriptine, she received a craniotomy to remove the pituitary macroadenoma. Pathological examination of the tumor revealed an acidophilic tumor. Postoperative radiotherapy was given for residual active tumor. She developed adrenal crisis two months after radiotherapy when she discontinued replacement therapy. The diagnosis of Hashimoto's thyroiditis was arrived at by palpation of the goiter, elevated thyroid antibodies, ultrasound pictures of the thyroid, fine needle aspiration cytology and hypothyroidism. To our knowledge, this is the first report of Albright's syndrome with Hashimoto's thyroiditis. The hypothesis of autoimmune disease is proposed to explain the hypofunction of the endocrine glands associated with Albright's syndrome.

Acromegaly↗
PubMed1990

Sonographic presentation in autoimmune thyroiditis.

We used real-time ultrasonography to examine 60 patients with autoimmune thyroiditis, then correlated the ultrasonic pictures with thyroid function, thyroid autoantibodies and fine needle aspiration cytology. In these 60 patients, 45 (75%) showed diffuse goiter, 6 (10%) showed multinodular goiter, and 9 (15%) had a solitary thyroid nodule sonographically. One of the 9 patients with a solitary nodule was a case of autoimmune thyroiditis combined with papillary carcinoma. The echogenicity of the thyroid was more than, the same as, or less than that of the adjacent muscles in 17, 22, and 21 patients, respectively. The groups were classified as hyperechoic, isoechoic, and hypoechoic, respectively. The mean serum T4 level was significantly lower in the hypoechoic group than in the hyperechoic or isoechoic groups (p less than 0.01 and p less than 0.05, respectively), and the incidence of hypothyroidism was significantly higher in the hypoechoic group than in the hyperechoic or isoechoic groups (p less than 0.001 and p less than 0.005, respectively). In addition, high titers of the antithyroid microsomal antibody (greater than or equal to 1280) were present more frequently in the hypoechoic group than in the hyperechoic or isoechoic groups (p less than 0.01 and p less than 0.05, respectively). There was no significant correlation between the cytomorphology and echogenicity of the thyroid in these cases. We conclude that sonography has two major uses in evaluating autoimmune thyroiditis: First, it is useful in excluding the coexistence of thyroid nodules; and second, marked hypoechogenicity of the thyroid implies an active cytotoxic autoimmune process and possibly a hypothyroid state.

Humans↗
PubMed1989

Visual, brainstem auditory and somatosensory evoked potential abnormalities in thyroid disease.

In order to investigate the neurophysiological effects of thyroid hormones, sixteen hypothyroid and twenty-seven hyperthyroid patients were studied for changes in visual, brainstem auditory and somatosensory evoked potentials. Hypothyroidism was associated with prolonged latency and reduced amplitude of visual evoked potential, prolonged latency and prolonged central conduction time of somatosensory evoked potential, and prolonged latency and interpeak latency of brainstem auditory evoked potential. Hyperthyroidism was associated with mild prolonged latency of visual evoked potential; other evoked potentials were normal. The prominent evoked potential abnormalities in hypothyroidism and mild evoked potential change in hyperthyroidism are consistent with a possibility that the central nervous system is more sensitive to a deficiency of thyroid hormone than to an excess.

Adolescent↗
PubMed1989

Serum prolactin and growth hormone response to thyrotropin-releasing hormone in patients with pituitary adenomas.

The dynamics of growth hormone (GH) and prolactin (PRL) secretion in response to intravenous 400 micrograms thyrotropin-releasing hormone (TRH) in 13 untreated patients with pituitary adenomas (6 women, 7 men; ages 20-64 years; 8 patients with acromegaly, 3 prolactinomas and 2 non-functional adenomas) were correlated with the results of immunohistochemical studies of GH and PRL in the adenoma cells. The basal serum GH concentrations were abnormally high in 6 and normal in 2 cases of acromegaly. In 5 of 6 acromegalic patients with pure GH-containing adenomas, TRH stimulated GH release by less than 100%. One patient with acromegaly and pancreatic islet cell carcinoma had the maximum increment for GH by 303%. TRH stimulated GH release by more than 100% in 2 acromegalic patients with mixed GH/PRL-containing adenomas. In 3 patients with prolactinoma and in 2 patients with non-functional adenoma the basal GH levels were 0.5 mU/L or undetectable and there was no GH response to TRH. The peak serum PRL levels after TRH were less than 100 ng/ml in 6 acromegalic patients with pure GH-containing tumors and in 2 patients with non-functioning pituitary tumors, and were more than 230 ng/ml in 3 patients with prolactinoma and in 2 acromegalic patients with mixed GH/PRL-containing tumors. It is suggested that the TRH test may help clinically in establishing the diagnosis of prolactinoma, pure GH-secreting tumors and mixed GH/PRL-containing tumors.

Adenoma↗
PubMed1989

Deficient erythrocyte membrane Gs alpha activity and resistance to trophic hormones of multiple endocrine organs in two cases of pseudohypoparathyroidism.

Patients with pseudohypoparathyroidism (PHPT) have been shown to have deficient cell membrane stimulatory GTP-binding regulatory protein activity (Gs activity) and other defects, which cause renal resistance to parathyroid hormone (PTH). Those patients also have a higher incidence of deficiency of other endocrine axes. To investigate the mechanisms of this syndrome on 2 patients, we measured erythrocytic ghost Gs activity by ADP-ribosylation method, which showed low and low normal levels for the 2 patients who were from the same family, suggesting type Ia of this syndrome. While basal T3, T4 and TSH were compatible with mild primary hypothyroidism in both patients, a TRH test showed exaggerated TSH responses. The estrogen, progesterone and testosterone levels were low and LH and FSH responses were marginally high, indicating gonadal resistance to gonadotropins. ACTH levels were also elevated and ACTH response to CRH was exaggerated in one patient, suggesting additional primary adrenal insufficiency. This finding indicates that systemic endocrine tests are essential for the management of PHPT patients who may have a deficiency of multiple endocrine axes subclinically.

Adolescent↗
PubMed1989

Effect of cranial irradiation on hypothalamus and pituitary functions.

Hypopituitarism can occur after cranial irradiation for tumors distant from the pituitary gland. Recent studies have suggested that this is hypothalamic in origin. Hypothalamic and pituitary functions were studied in 11 patients, 4 men and 7 women, 4.5 years or more after radiotherapy for nasopharyngeal carcinomas. The estimated average total dose was 5000 cGys for the hypothalamus and pituitary gland. Except for 2 women with amenorrhea and 4 men with impotency, the patients did not have evident endocrine deficiency. Baseline hormone profiles revealed normal T4, T3 and cortisol levels, 6 with elevated prolactin, 3 with reduced testosterone and 3 with slightly elevated basal TSH. The four menopausal women had impaired gonadotropin response to LHRH (100 micrograms, i.v.). Four (1 menstruating, 1 amenorrheic, 2 menopausal) women did not reach peak FSH response 4 hours after LHRH injection. The other amenorrheic woman had minimal FSH and LH response to LHRH which persisted even after 8 days of pulsatile infusion of LHRH (1 microgram/90min). TSH response to TRH (400 micrograms, i.v.) was delayed in 7 patients. GH response to human GRH (1 microgram/kg, i.v.) was impaired in 6 patients (maximal GH less than 5 mU/l). ACTH response to ovine CRH (1 microgram/kg, i.v.) was impaired in 3 patients (less than 50% elevation from baseline). Three patients who had normal GRH tests had impaired GH response to insulin hypoglycemia. Six patients had an empty sella on CT scan. From this study the following conclusions are drawn: (1) Among the four axes, GH is the most vulnerable. (2) The insulin tolerance test is still the best single test for evaluation of hypothalamic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Association of HLA-DR tissue types with Graves' disease in Taiwan.

To determine the association of HLA-DR tissue types and Graves' disease (GD) in Chinese residing in Taiwan, we studied HLA-DR antigens on 93 unrelated patients with Graves' disease, and 106 normal persons (N). The prevalence of DR2 (GD: 40.9%, N: 21.7%, pc = 0.028 where pc is the Fisher's probability times the numbers of antigens considered), DR9 (GD: 29%, N: 13.2%, pc = 0.048), DQw1 (GD: 58.1%, N: 39.6%, pc less than 0.003) and DRw53 (GD: 58.1%, N: 41.5%, pc less than 0.002) were significantly increased in patients with Graves' disease, while the prevalence was decreased significantly for DR3 (GD: 16.1%, N: 33.0%, pc = 0.031) and DRw52 (GD: 58.1%, N: 76.4%, pc = 0.01). When the combinations of DR2, DR3 and DR9 were compared with other HLA-DR antigens, DR3 remained less prevalent in GD; DR2/9 heterozygotes were strongly associated with GD; while neither DR2 nor DR9 remained significantly associated with GD when DR2/9 heterozygotes were removed from each. When we separated the patients into subgroups according to the onset of clinical symptoms occurring by the age of 35 years, there was no significant difference in the frequencies of HLA-DR antigens in those two subgroups. Patients with or without exophthalmos, antimicrosomal antibody or antithyroglobulin antibody had similar distribution of HLA-DR types. Our data suggested that in our area DR2 and DR9 played additive roles in the susceptibility of Graves' disease.

Adolescent↗